Death rattle—the noisy breathing caused by mucus and relaxing airways that occurs frequently in dying patients—was significantly reduced in people treated with prophylactic subcutaneous scopolamine butylbromide, the SILENCE randomized clinical trial showed.
Death rattle occurred in 13% of subjects in the scopolamine butylbromide group versus 27% in the placebo group (difference 14%, 95% CI 2%-27%, P=0.02), reported Harriëtte van Esch, MD, of Erasmus Medical Center in Rotterdam, the Netherlands, and co-authors in JAMA.
Scopolamine butylbromide is an anticholinergic medication not approved in the U.S. Also known as hyoscine butylbromide, the drug does not cross the blood-brain barrier, unlike the formulation used in approved scopolamine patches.
“Anticholinergics decrease the production of mucus and therefore do not affect existing mucus; thus administering an anticholinergic drug after the onset of a death rattle may be less effective than prophylactic use (i.e., before its onset),” van Esch and colleagues wrote.
Of 163 patients in six hospices in the Netherlands from April 2017 through December 2019, the final analysis included 157 patients (median age 76; 56% women) accurately identified as entering an actively dying phase, when death was imminent, as determined by hospice clinicians based on Dutch guidelines.
Factors included being bedbound, unable to swallow, and being semi-comatose. Patients receiving the intervention were systematically evaluated with the physiologic variables of the Dutch Care Program For the Dying every 4 hours and assessed with a death rattle scale and a measure of restlessness.
When patients were considered to be actively dying, they were randomized to either placebo (n=78) or scopolamine butylbromide 20 mg subcutaneously (n=79) four times a day, which was continued until death or the appearance of a rattle audible at the foot of the bed or farther away. This was considered a grade 2 rattle; by comparison, no rattle was grade 0; rattle audible close to the patient was grade 1; and rattle audible at the door to the room was grade 3. The primary end point was a grade 2 rattle present at two time points 4 hours apart.
Time from entering the dying phase to death rattle showed a lower instantaneous risk of death rattle in the scopolamine butylbromide group, with a subdistribution HR of 0.44 (95% CI 0.20-0.92, P=0.03). The cumulative incidence of death rattle at 48 hours was 8% in the scopolamine butylbromide group versus 17% in the placebo group.
In the scopolamine group, restlessness occurred in 28% compared with 23% in the placebo group; dry mouth in 10% compared with 15% for placebo; and urinary retention in 23% versus 17% for placebo.
An exploratory analysis found a significantly longer dying phase in the scopolamine butylbromide group (median 42.8 hours, IQR 20.9-80.1 hours) versus placebo (median 29.5 hours, IQR 21.1-41.7 hours). No significant difference was seen in the use of opioids, haloperidol, or sedatives, or for instantaneous risk of pain, dyspnea, nausea, or vomiting.
Many clinicians question whether the death rattle should be treated, noted Jared Lowe, MD, and Laura Hanson, MD, MPH, both of the University of North Carolina School of Medicine at Chapel Hill, in an accompanying editorial.
“One argument is that there is no evidence to suggest this sign is distressing to a patient, and interventions may be costly and burdensome,” Lowe and Hanson wrote.
“One counter argument is to embrace humility and acknowledge that the internal experience of the dying, nonverbal patient cannot be fully known, but when in doubt regarding comfort, it is best to try treatment,” they continued. “Another reason to consider treatment for a death rattle is that the patient’s noisy respiration can have negative effects on family members and other observers.”
“The SILENCE trial focuses on improving an outcome important to family and other caregivers,” Lowe and Hanson added. “This study is powerful reminder that evidence-based hospice and palliative care requires new research to deepen the understanding of best practices for end-of-life care.”
“Performing an RCT with patients who are in the dying phase can be challenging,” van Esch and co-authors observed. “However, this study shows that a randomized clinical trial is feasible in the context of daily hospice care. This process can be facilitated by using advance consent, appointing the hospice’s physician as local researcher, and integrating outcome assessments into a digital, structured template used for monitoring patient care in the dying phase.”
Limitations of the study included the presence of a death rattle prior to clinician-determined onset of the dying phase in some patients.
“The dying phase was recognized based on a Dutch guideline regarding care in the dying phase, which places the decision primarily in the hands of health care professionals,” the researchers acknowledged. “However, given that no validated tool currently exists for assessing the onset of the dying phase, a death rattle likely cannot be prevented in every dying patient.”
The study results also may have limited applicability to change current practice, particularly in the U.S., the editorialists pointed out. The intervention required intermittent subcutaneous medication administration, which is generally restricted to in-patient care.
Scopolamine butylbromide is a compound distinct from scopolamine administered transdermally, Lowe and Hanson added. “This suggests that the adverse effect profile of these products differs, and the safety demonstrated in this study may not generalize to other formulations,” they wrote.
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Death rattle—the noisy breathing caused by mucus and relaxing airways that occurs frequently in dying patients—was significantly reduced in patients treated with subcutaneous scopolamine butylbromide, a randomized trial showed.
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The study results may have limited applicability to change current practice, particularly in the U.S. where the drug is not approved.
Paul Smyth, MD, Contributing Writer, BreakingMED™
This study was supported by the Palliative Care Research Programme Palliantie from the Netherlands Organization for Health Research and Development. Additional support was provided by Laurens Zorg in Balans and Stichting Voorzieningenfonds Calando.
van Esch reported receiving grants from Laurens Zorg in Balans during the conduct of the study.
The editorialists reported no disclosures.
Cat ID: 925
Topic ID: 915,925,728,791,730,192,925
